Patients with Epstein–Fechtner syndromes owing to MYH9 R702 mutations develop progressive proteinuric renal disease

Sekine, Takashi; Konno, Mutsuko; Sasaki, Satoshi; Moritani, Suzuko; Miura, Takuma; Wong, Wai Keung; Nishio, Hisanori; Nishiguchi, Toshihiro; Ohuchi, Miyako Yoshinari; Tsuchiya, Shigeru; Matsuyama, Tomohiro; Kanegane, Hirokazu; Ida, Komei; Miura, Kenichiro; Harita, Yutaka; Hattori, Motoshi; Horita, Shigeru; Igarashi, Takashi; Saito, Hidehiko; Kunishima, Shinji

doi:10.1038/ki.2010.21

Cited by 88 publications

(113 citation statements)

References 24 publications

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“…To demonstrate the utility of our method to detect glomerular dysfunction, we measured the simultaneous vascular clearance of dextrans after knockdown of zMyh9 and zApol1, respectively. Mutations in MYH9 and APOL1 are associated with chronic kidney disease in humans (3,8). However, it remains unclear whether zMyh9 and zApol1 serve similar or identical functions in zebrafish.…”

Section: ϫ19mentioning

confidence: 99%

Simultaneous assessment of glomerular filtration and barrier function in live zebrafish

Kotb

Müller

Xie

et al. 2014

American Journal of Physiology-Renal Physiology

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brafish pronephros is a well-established model to study glomerular development, structure, and function. A few methods have been described to evaluate glomerular barrier function in zebrafish larvae so far. However, there is a need to assess glomerular filtration as well.In the present study, we extended the available methods by simultaneously measuring the intravascular clearances of Alexa fluor 647-conjugated 10-kDa dextran and FITC-conjugated 500-kDa dextran as indicators of glomerular filtration and barrier function, respectively. After intravascular injection of the dextrans, mean fluorescence intensities of both dextrans were measured in the cardinal vein of living zebrafish (4 days postfertilization) by confocal microscopy over time. We demonstrated that injected 10-kDa dextran was rapidly cleared from the circulation, became visible in the lumen of the pronephric tubule, quickly accumulated in tubular cells, and was detectably excreted at the cloaca. In contrast, 500-kDa dextran could not be visualized in the tubule at any time point. To check whether alterations in glomerular function can be quantified by our method, we injected morpholino oligonucleotides (MOs) against zebrafish nonmuscle myosin heavy chain IIA (zMyh9) or apolipoprotein L1 (zApol1). While glomerular filtration was reduced in zebrafish nonmuscle myosin heavy chain IIA MO-injected larvae, glomerular barrier function remained intact. In contrast, in zebrafish apolipoprotein L1 MO-injected larvae, glomerular barrier function was compromised as 500-kDa dextran disappeared from the circulation and became visible in tubular cells. In summary, we present a novel method that allows to simultaneously assess glomerular filtration and barrier function in live zebrafish. glomerular filtration; in vivo observations; kidney; pronephros; zebrafish GENOME-WIDE CLINICAL SCREENINGS have produced numerous gene candidates that are currently being discussed for their relevance as risk factors for chronic kidney disease (5). Validating such candidates in mouse knockout models, however, is an expensive and time-consuming task. It would therefore be of great interest to establish a rapid screening method that is easy to handle, accurate, and dependable. The zebrafish seems to ideally fulfill this request. The zebrafish pronephros contains a single glomerulus that is structurally identical to mouse and human glomeruli and is fully developed after 3-4 days (1, 6). Moreover, its high reproduction rate and the possibility of knocking down specific genes via injection of morpholino oligonucleotides (MOs) make the zebrafish ideally suited for rapid screening experiments. Being highly transparent, the zebrafish larva is a powerful model for microscopy-based in vivo analysis of the integrity of the glomerular filtration barrier. However, whereas routine assays of fluorescent dextran clearance have been established for the mouse (12), the same degree of reliability has yet to be reached working with zebrafish larvae.In most studies, defects of the filtration barrier in...

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Section: ϫ19mentioning

confidence: 99%

Simultaneous assessment of glomerular filtration and barrier function in live zebrafish

Kotb

Müller

Xie

et al. 2014

American Journal of Physiology-Renal Physiology

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“…Previous work from human patients has suggested that the abnormalities found in the kidneys could reflect defects in the podocytes. 24 NMII-A partially colocalizes with the podocyte marker, synaptopodin in both A gfp /A ϩ and A gfpR702C /A ϩ glomeruli ( Figure 7C). Figure 7D provides evidence for altered podocyte architecture, typically foot process effacement, that is seen in the A D1424N /A D1424N mice.…”

Section: Kidney Abnormalities In the Point Mutant And Nmii-a Podocytementioning

confidence: 99%

Mouse models of MYH9-related disease: mutations in nonmuscle myosin II-A

Zhang

Conti

Malide

et al. 2012

Blood

157

187

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We have generated 3 mouse lines, each with a different mutation in the nonmuscle myosin II-A gene, Myh9 (R702C, D1424N, and E1841K). Each line develops MYH9-related disease similar to that found in human patients. R702C mutant human cDNA fused with green fluorescent protein was introduced into the first coding exon of Myh9, and D1424N and E1841K mutations were introduced directly into the corresponding exons. Homozygous R702C mice die at embryonic day 10.5-11.5, whereas homozygous D1424N and E1841K mice are viable. All heterozygous and homozygous mutant mice show macrothrombocytopenia with prolonged bleeding times, a defect in clot retraction, and increased extramedullary megakaryocytes. Studies of cultured megakaryocytes and live-cell imaging of megakaryocytes in the BM show that heterozygous R702C megakaryocytes form fewer and shorter proplatelets with less branching and larger buds. The results indicate that disrupted proplatelet formation contributes to the macrothrombocytopenia in mice and most probably in humans. We also observed premature cataract formation, kidney abnormalities, including albuminuria, focal segmental glomerulosclerosis and progressive kidney disease, and mild hearing loss. Our results show that heterozygous mice with mutations in the myosin motor or filament-forming domain manifest similar hematologic, eye, and kidney phenotypes to humans with MYH9-related disease. (Blood. 2012;119(1): 238-250) IntroductionPoint mutations in MYH9, the gene encoding nonmuscle myosin heavy chain II-A (NMHCII-A), underlie autosomal dominant syndromes in humans (incidence, ϳ 1 in 500 000). 1-3 The human abnormalities manifest as macrothrombocytopenia, granulocyte inclusions, progressive proteinuric renal disease, cataracts, and sensorineural deafness. Most patients have a mild bleeding tendency. Patients may develop early or late onset deafness, cataracts, and progressive glomerulosclerosis, leading to kidney failure. These syndromes, now referred to as MYH9-related diseases (MYH9-RDs), were formerly called May-Hegglin, Fechtner, Sebastian, and Epstein syndromes. 1,4 Each nonmuscle myosin II (NMII) molecule is composed of a pair of heavy chains (M r ϭ 230 000) and 2 pairs of light chains (M r 20 000 and 17 000). NMII has 3 paralogs, NMII-A, NMII-Bm and NMII-C, whose heavy chains are encoded by 3 different genes MYH9, MYH10, and MYH14, respectively, located on 3 different human chromosomes (22, 17, and 19). NMIIs are ubiquitously expressed but differ with respect to localization and expression levels in cells, although they may also overlap with each other. 5 The NMII protein is markedly asymmetric with a globular-shaped motor domain at one end containing the enzymatic activity that hydrolyzes MgATP to convert chemical energy into the mechanical translocation of actin filaments. The other end of the molecule is a long ␣-helical rod that dimerizes the 2 heavy chains and participates in the formation of bipolar filaments, composed of ϳ 28 molecules, 6 which are required for most NMII functions. As a motor prote...

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“…Первые проявления нефропатии -протеинурия и микрогематурия, однако гематурия может быть и про-явлением тромбоцитопении [6,7,[17][18][19].…”

Section: рисунокunclassified

MYH9-related inherited thrombocytopenia

Suntsova¹,

Калинина²,

Аксёнова³

et al. 2017

VGOIP

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Вопросы гематологии/онкологии и иммунопатологии в педиатрии № Одна из форм наследственной тромбоцитопении (НТ) -тромбоцитопения, ассоциированная с мутацией в гене MYH9, кодирующем синтез тяжелой цепи немышечного миозина IIA. Она объеди-няет группу заболеваний: аномалия Мея-Хегглина, синдром Эпштейна, синдром Фехтнера, син-дром Себастьяна, которые характеризуются изолированной тромбоцитопенией с большими или гигантскими формами тромбоцитов, проявляющейся геморрагическим синдромом различной сте-пени выраженности, и развитием негематологических проявлений в виде повышенного риска раз-вития нейросенсорной тугоухости, ранней катаракты и прогрессирующей нефропатии. Обнару-жение больших форм тромбоцитов в мазках периферической крови и специфических включений в нейтрофилах при иммунофлюоресцентном окрашивании -простые методы ранней диагности-ки этой формы НТ, а молекулярно-генетическое исследование помогает в поиске специфиче-ской мутации. В статье представлен клинический случай: ребенок, 9 лет, с НТ, ассоциированной с мутацией в гене MYH9, с характерными клиническими проявлениями, подтвержденной с помо-щью молекулярно-генетического исследования. Показано, что применение агонистов тромбо-поэтиновых рецепторов (рТПО) может быть эффективным методом профилактики кровотечений при данной форме НТ. Inherited thrombocytopenia caused by mutations in MYH9 gene, is one of the forms of inherited platelet disorders. Currently, it comprises a group of diseases previously known as: Mey-Hegglin anomaly, Epstein syndrome, Fechtner syndrome, Sebastian syndrome. These syndromes are characterized by macrothrombocytopenia, and development of non-hematological manifestations such as sensorineural hearing loss, cataract and progressive nephropathy. Finding of large forms of platelets in blood smears and specific inclusions in neutrophils in immunofluorescence staining are simple methods for early diagnosis of this form of inherited thrombocytopenia, molecular-genetic analysis helps to detect the specific mutations. This article is described a clinical case of a 9-years old child with MYH9-related inherited thrombocytopenia, having typical clinical picture and confirmed by molecular-genetic analysis. It illustrated that the administration of agonist TPO-receptors may be effective for prevention of bleeding in this form of inherited thrombocytopenia. MYH9-related inherited thrombocytopeniaE

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Patients with Epstein–Fechtner syndromes owing to MYH9 R702 mutations develop progressive proteinuric renal disease

Cited by 88 publications

References 24 publications

Simultaneous assessment of glomerular filtration and barrier function in live zebrafish

Simultaneous assessment of glomerular filtration and barrier function in live zebrafish

Mouse models of MYH9-related disease: mutations in nonmuscle myosin II-A

MYH9-related inherited thrombocytopenia

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